Title of Invention

PROCESS FOR THE PREPARATION OF 3-VINYL CEPHALOSPORIN COMPOUND

Abstract The present invention provides an improved process for the preparation of cefixime of formula (I). The said process comprising the steps of: c in water and an organic solvent using salt of weak organic acid at a temperature in the range of 0°C to 35°C, (ii) hydrolysing this solution with sodium hydroxide at a temperature in the range of 0°C to 25°C, (iii) adjusting the pH of resultant mass to 2.0 to 3.0 with dilute acid in the presence or absence of solvent at a temperature in the range of 10°C to 45°C, to isolate the crude cefixime of formula (I), (iv) dissolving the crude cefixime of formula (I) in water using ammonia solution, and (v) precipitating the product by adjusting pH of the solution to 2.0 to 3.0 using HCl in the presence of water miscible solvent to get cefixime of formula (I) in pure form.
Full Text

Field of the invention
The present invention relates to a process for the preparation of an orally active cephalosporin antibiotic. The present invention more particularly relates to an improved process for the preparation of cefixime of the formula (I).

Description of the prior art
Cefixime is an orally active third-generation cephalosporin antibiotic and is more potent against gram-negative bacteria. Preparation of the compound of formula (I) involves condensation of 7-amino-3-vinyl-3-cephem-4-carboxylic acid with the derivative of (Z)-2-amino-a-( 1 -methoxycarbonylmethoxyimino)-4-thiazole acetic acid to produce methyl ester compound of formula (II),

followed by hydrolysis to produce the title compound.
GB 2 330 140 discloses a process for the preparation of the compound of formula (I) which comprises treating the compound of formula (II) with Na2CO3 in DMF and water, which has the following problems: (i) color of product was poor, (ii) fails in residual solvent i.e. DMF, (iii) poor quality of product.
GB 2 330 141 discloses a process for the preparation of the compound of formula (I) which comprises treating the compound of formula (II) in an organic solvent with aqueous solution of Na2CO3 and phase transfer catalyst, the bi-phasic

reaction has the following problems: (i) color of product was poor, (ii) poor quality and yield of product.
In US patent 4,409,214 and WO 95/33753 discloses the process for the preparation of cefixime in which the hydrolysis step involves the use of hazardous triflnoroacetic acid and anisole. In WO 99/52913 the hydrolysis step along with deblocking the amino protective group and carboxylate protective group involves the use of phenol and protonic acid. The steps described in the above patents are more complicated and also suffer from low yield and poor quality.
J.Antibiotics (1985), 38, 1738 discloses various processes for the preparation of cefixime of formula (I). The processes involve the use of column for purification thereby suffers in poor yield. Column purification cannot be used in large-scale operations, there by making the process non-commercial.
We have now found an improved process for the preparation of the compound of formula (I), which process has advantages over the processes described in the above-mentioned prior art documents.
Objectives of the invention
The main objective of the present invention is to provide a process for the preparation of cefixime formula (I), which has better quality such as color and solubility.
Another objective of the present invention is to provide a process for the preparation of compounds of formula (I), which avoid use of hazardous chemicals like TFA and also easy to implement on commercial scales.
Still another objective of the present invention is to provide a process for the preparation of compounds of formula (I) in good yield and high purity, which complies as per USP/BP.
Yet another objective of the present invention is to provide a process for the purification of crude cefixime.

Summary of the invention:
Accordingly, the present invention provides an improved process for the preparation of Cefixime of formula (I), which comprises the steps of:

in water and an organic solvent using salt of weak organic acid at a temperature in the range of 0oC to 35°C,
(ii) hydrolysing this solution with sodium hydroxide at a temperature in the range of 0°C to 25°C,
(iii) adjusting the pH of resultant mass to 2.0 to 3.0 with dilute acid in the presence or absence of solvent at a temperature in the range of 10°C to 45°C, to isolate the crude cefixime of formula (I),
(iv) dissolving the crude cefixime of formula (I) in water using ammonia solution, and
(v) precipitating the product by adjusting pH of the solution using HCl in the presence of water miscible solvent to get cefixime of formula (I) in pure form.

Detailed description of the invention
In an embodiment of the present invention the organic solvent used in step (i) is selected from acetone, methanol, THF, ethyl acetate, MDC; preferably acetone and water.
In another embodiment of the present invention the salt of weak organic acid is selected from sodium acetate, sodium lactate, sodium citrate, sodium maleate, sodium lactate or sodium fumarate; preferably sodium acetate.
In yet another embodiment of the present invention the above said reaction mass may be treated with sodium hydroxide solution at a temperature in the range of 0°C to 25°C, more particularly from 0°C to 1°C in aqueous medium.
In still another embodiment of the present invention the product may be isolated by adjusting pH to 2.0 to 3.0, by using dilute HCl, H2SO4 and orthophosphoric acid, more particularly to pH 2.5±0.05.
In yet another embodiment of the present invention the water miscible solvent used in step (v) is selected from acetone, methanol, THF, and the like
In another embodiment of the present invention, the compound of formula
(I) obtained is in trihydrate form.
In yet another embodiment of the present invention, the compound of formula (I) obtained is syn isomer.
In an embodiment of the present invention the starting material of formula
(II) can be prepared from the processes known in the prior art.
The present invention is exemplified by the following example, which is provided for illustration only and should not be construed to limit the scope of the invention.

Example I;
Preparation of [6R-[6(x,7p(Z)]-7-[2-amino-4-thiazolyl[(carboxymethoxy) imino]acetyl]amino]-3-vinyl-3-cephem-4-carboxylic acid.
To, [6R-[6a,7p(Z)]]-7-[[(2-amino-4-thiazolyl)[(methoxycarbonyl methoxy) imino]acetyl]amino]-3-vinyl-3-cephem-4-carboxylic acid compound of formula (II) (100 gm) in distilled water (1000 ml) and acetone (500 ml), sodium acetate
(64 gm) was slowly added at 28 - 30 °C till clear solution obtained. The solution was cooled to 0 - 1°C and 18 % sodium hydroxide solution (150 ml) was added. The resultant solution was stirred at 5 - 8°C till the completion of reaction. pH of reaction mass was adjusted to 4.8 - 5.0 with 18% aqueous HCl acid solution.. The pH of solution was adjusted to 2.45 to 2.55 with 8-10% dil. HCl acid at 5 - 6° C. The reaction mass temperature was raised to 30 - 32°C and stirred for 180 minutes and then cooled to 1 - 3°C. The crude product obtained was filtered. The crude product was dissolved in water using ammonia solution. The solution was subjected to carbon treatment and then carbon was filtered, washed the bed with water. To the clear solution acetone was added and pH of the solution was adjusted to 2.45 to 2.55 with 8-10% dil. HCl acid at 5 - 6°C. the pure product thus obtained was filtered and washed the wet product with water (150 ml) and dried under vacuum to get the title compound in pure form (98-100 gm).
Example II;
Purification of crude [6R-I6a,7P(Z)]-7-[2-amino-4-
thiazolyl[(carboxymethoxy) imino]acety!]amino]-3-yinyl-3-cephem-4-
carboxylic acid (Cefixime)
To the crude [6R-[6a,7p(Z)]-7-[2-amino-4-thiazolyl[(carboxymethoxy) imino]acetyl]amino]-3-vinyl-3-cephem-4-carboxylic acid (50 gm) in water (450 ml) ammonia solution was added to adjust the pH 5.5 to 6.0 at 15°C. The solution

was cooled to 6 - 8°C and subjected to carbon treatment and then carbon was filtered, washed the bed with water. To the clear solution acetone (200 ml) and water (200 ml) were added and pH of the solution was adjusted to 2.45 to 2.55 with 8-10% dil. HCl acid at 5 - 6*^ C. The pure product thus obtained was filtered and washed the wet product with water (150 ml) and dried under vacuum to get the title compound in pure form (40-43 gm).



We Claim:
1. A process for the preparation of the compound of formula (I)

the said process comprising the steps of:
(i) dissolving the methyl ester compound of formula (II)

in water and an organic solvent using salt of weak organic acid at a temperature in the range of 0°C to 35°C,
(ii) hydrolysing this solution with sodium hydroxide at a temperature in the range of 0°C to 25°C,
(iii) adjusting the pH of resultant mass to 2.0 to 3.0 with dilute acid in the presence or absence of solvent at a temperature in the range of 10°C to 45 °C, to isolate the crude cefixime of formula (I),
(iv) dissolving the crude cefixime of formula (I) in water using ammonia solution, and
(v) precipitating the product by adjusting pH of the solution to 2.0 to 3.0 using HCl in the presence of water miscible solvent to get cefixime of formula (I) in pure form.

2. The process as claimed in claim 1, wherein the organic solvent used in step (i) is selected from acetone, methanol, THF, ethyl acetate, or MDC.
3. The process as claimed in claim 1, wherein the salt of weak organic acid used in step (i) is such as sodium acetate, sodium lactate, sodium citrate, sodium maleate, or sodium fumarate.
4. The process claimed in claim 1, wherein the reaction temperature for step (ii)is 0°C to 1°C.
5. The process as claimed in claim 1, wherein the pH for isolation is 2.5±0.05.
6. The process as claimed in claim 1, wherein the water miscible solvent used in step (i) is selected from acetone, methanol, or THF.
7. The process as claimed in claim 1, wherein cefixime of formula (I) is in trihydrate form.
8. The process as claimed in claim 1, wherein cefixime of formula (I) obtained is a syn isomer.
9. A process for the purification of crude cefixime of formula (I) comprising the steps of:

(a) dissolving the cefixime of formula (I) in water using ammonia solution,
(b) precipitating the product by adjusting pH of the solution to 2.0 to 3.0 using HCl in the presence of acetone to get cefixime of formula (I) in pure form.


Documents:

311-CHE-2004 EXAMINATION REPORT REPLY RECIEVED 25-02-2010.pdf

311-che-2004-abstract.pdf

311-che-2004-claims.pdf

311-che-2004-correspondnece-others.pdf

311-che-2004-description(complete).pdf

311-che-2004-form 1.pdf

311-che-2004-form 5.pdf


Patent Number 244708
Indian Patent Application Number 311/CHE/2004
PG Journal Number 52/2010
Publication Date 24-Dec-2010
Grant Date 16-Dec-2010
Date of Filing 02-Apr-2004
Name of Patentee ORCHID CHEMICALS & PHARMACEUTICALS LTD
Applicant Address ORCHID TOWERS, 313, VALLUVAR KOTTAM HIGH ROAD, NUNGAMBAKKAM-600 034, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 GAUTAM KUMAR DAS GEETHA APARTMENTS 33, RUKMINI ROAD, KALAKSHETRA COLONY, BESANTNAGAR, CHENNAI-600 090, TAMILNADU, INDIA.
2 PRAMOD NARAYAN DESHPANDE 5-TAMPLE GLADE APARTMENTS, 41-D, BEACH ROAD, KALAKSHETRA COLONEY, BESANT NAGAR, CHENNAI-600 090, TAMILNADU, INDIA.
3 RAJENDRA JANARDAN SARANGDHAR PLOT NO. 8 (OLD), NEW NO. 19, ELEGANT APARTMENTS, DR. VASUDAVE NAGAR EXTENSION, THIRUVANMIYUR, CHENNAI-600 041, INDIA.
4 JOHN MUTHIAH RAJA JEYAKUMAR 34, 3RD MAIN ROAD, ANNA NAGAR, CHENAGALPATTU-603 001, TAMILNADU, INDIA.
PCT International Classification Number C12N15/03
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA